Linezolid—crystal form II

ABSTRACT

The invention is a novel crystal form (Form II) of a known compound, linezolidwhich is useful as an antibacterial agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.09/772,239, filed Jan. 29, 2001 now U.S. Pat. No. 6,444,813 and claimsthe benefit of the following provisional application: U.S. Ser. No.60/179,837, filed Feb. 2, 2000, under 35 USC §119(e)(i).

BACKGROUND OF THE INVENTION

1. Field of the Invention

The field of the invention is a novel crystal form of a known compound,linezolid which is pharmaceutically useful as an antibacterial agent.

2. Description of the Related Art

U.S. Pat. No. 5,688,792 discloses the antibacterial agent linezolid aswell as a process for its preparation. EXAMPLE 5 reports the linezolidproduced had a mp of 181.5-182.5°.

There are many other disclosures of processes to prepare linezolid. J.Med. Chem., 39(3), 673-9 (1996) reports the linezolid was,“recrystallized from ethyl acetate and hexanes . . . white crystals,m.p. 181.5-182.5C.” It also sets forth the IR spectrum as “3284, 3092,1753, 1728, 1649, 1565, 1519, 1447, 1435”.

Tetrahedron Lett., 40(26), 4855 (1999) discloses linezolid and a processto prepare linezolid. However, this document does not set forth themelting point or IR spectrum of the linezolid prepared.

U.S. Pat. No. 5,837,870 (International Publication WO97/37980 ofPCT/US97/03458) discloses a process to prepare linezolid. Linezolid isdescribed in EXAMPLE 18, which does not set forth the melting point orIR spectrum of the linezolid prepared.

International Publication WO99/24393 of PCT/US98/20934 discloses aprocess to prepare linezolid. Linezolid is described in EXAMPLES 8, 9and 12 which do no set forth the melting point or IR spectrum of thelinezolid prepared.

The form of linezolid being used in the clinical trials to support thefiling of the NDA is Form II.

SUMMARY OF INVENTION

Disclosed is a(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,crystal “Form II” with a powder X-ray diffraction spectrum of:

d-Spacing (Á) Two-Theta Angle (°) Relative Intensity (%) 12.44 7.10 29.26 9.54 9 6.37 13.88 6 6.22 14.23 24 5.48 16.18 3 5.28 16.79 100 5.0117.69 2 4.57 19.41 4 4.50 19.69 2 4.45 19.93 6 4.11 21.61 15 3.97 22.3923 3.89 22.84 4 3.78 23.52 7 3.68 24.16 1 3.52 25.28 13 3.34 26.66 13.30 27.01 3 3.21 27.77 1

Also disclosed is(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,crystal “Form II” with an infrared (IR) spectrum as a mineral oil mull:3364, 1748, 1675, 1537, 1517, 1445, 1410, 1401, 1358, 1329, 1287, 1274,1253, 1237, 1221, 1145, 1130, 1123, 1116, 1078, 1066, 1049, 907, 852 and758 cm⁻¹.

Further disclosed is a process to prepare(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,crystal “Form II ” which comprises:

(1) producing(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamidein greater than 98% enantiomeric purity,

(2) mixing the greater than 98% enantiomerically pure(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamidein a solvent or mixture of solvents at a temperature below a temperatureof about 80° and

(3) separating the(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamidecrystal “Form II” from the solvent(s).

DETAILED DESCRIPTION OF THE INVENTION

Linezolid,(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,is a known pharmaceutically useful antibacterial agent, see U.S. Pat.No. 5,688,792 (EXAMPLE 5). Linezolid can be used orally or given by IVas a sterile solution.

When linezolid was originally produced, the crystal form was Form I.Form II differs from Form I in its IR spectrum, X-ray powder diffractionspectrum and melting point.

Once linezolid is synthesized, crystal Form II is prepared by startingwith linezolid of high enantiomeric purity. It is preferred that thelinezolid be more than 98% enantiomerically pure, it is more preferredthat the linezolid be more than 99% pure and it is even more preferredthat the linezolid be 99.5% pure. The linezolid of greater than 98%enantiomeric purity to be used to form crystal form II can either be insolution or be a solid. The linezolid starting material, solid orsolution, is mixed with a solvent selected from the group consisting of:

water,

acetonitrile,

chloroform, methylene chloride, toluene,

R₁—OH where R₁ is C₁-C₆ alkyl,

R₁—CO—R₂ where R₂ is C₁-C₆ alkyl or phenyl substituted with 1 thru 3 R₁where R₁ is as defined above, and where R₁ is as defined above,

R₁—CO—O—R₂ where R₁ is C₁-C₆ alkyl and R₁ is as defined above,

R₁—O—R₂ where R_(1 is C) ₁-C₆ alkyl and R₁ is as defined above. It ispreferred that the solvent be selected from the group consisting ofwater, ethyl acetate, methanol, ethanol, propanol, i-propanol, butanol,acetonitrile, acetone, methyl ethyl ketone, chloroform, methylenechloride, toluene, xylene, diethyl ether, or methyl-t-butyl ether. It ismore preferred that the solvent be ethyl acetate, acetone, acetonitrile,propanol, or isopropanol. It is most preferred that the solvent be ethylacetate.

The mixture of linezolid in the solvent is agitated at a temperaturebelow 80° until crystals of Form II are formed and crystals of othersolid forms, such as Form I, disappear. It is preferred to dissolve thelinezolid in ethyl acetate at a temperature near the boiling point ofthe solvent. This mixture is cooled to a temperature of about 70°. Themixture may be seeded with crystals of Form II to facilitatecrystallization. It is preferred that the solid product is cooled andagitated at a temperature between about 45° and about 60° until thesolids consist only of Form II crystals. It is most preferred tomaintain the slurry at a temperature of about 55°. It is preferred tomix the linezolid and solvent for at least 10 min, it is even morepreferred to mix the linezolid and solvent for at least 20 min and it ismost preferred to mix the linezolid and solvent for at least 30 min. Thetime and temperature will vary depending on the solvent selected. Withethyl acetate it is preferred to mix for not less that 60 minutes.

The crystalline slurry may be further cooled to improve yield, and thesolid Form II product may be isolated. The mixture may be further cooledand agitated. Other measures which can be used to facilitatecrystallization include, but are not limited to, cooling, concentrationof the solution by evaporation or distillation, or through addition ofother solvents.

The crystals are isolated by procedures known to those skilled in theart.

Crystal Form II is the most stable form below about 85°. It is preferredto use starting material with less than 0.2% of the R enantiomer oflinezolid to minimize or eliminate the formation of a pseudoracemicsolid solution of the two enantiomers which tends to crystallize as theForm I solid, even at temperatures below 85°.

It is well known to those skilled in the art that linezolid is useful asan antibacterial agent, see for example U.S. Pat. No. 5,688,792.

DEFINITIONS AND CONVENTIONS

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

DEFINlTIONS

Linezolid refers to(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamidethe compound of formula:

All temperatures are in degrees Centigrade.

IR refers to infrared spectroscopy.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of thesolid to the solvent is weight/volume (wt/v).

The term C₁-C₆ alkyl means alkyl of 1 thru 6 carbon atoms and isomersthereof where such exist.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

Example 1 Preparation of Crystal Form II of Linezolid

Linezolid with better than 99.8% enantiomeric purity, less than 0.2% ofthe R enantiomer, (1.99 grams) is mixed with ethyl acetate (100 mL). Theflask is stoppered and heated to 65° with constant stirring in atemperature controlled oil bath. The linezolid is completely dissolvedand the mixture is stirred for an additional 10 minutes. The temperatureis maintained at 55° in the flask and one neck of the flask isunstoppered to allow slow evaporation of the solvent. A gentle stream ofnitrogen is blown across the open neck to aid in evaporation. Solidsspontaneously precipitated from solution and the volume is reduced byabout 25% of the initial volume. The flask is sealed and mixed for 90minutes while maintaining the mixture at 55°. The mixture was thencooled to about 23° while being stirred. The solids are isolated byvacuum filtration using a sintered glass funnel to give linezolid incrystal form. Analysis by powder X-ray diffraction indicates that thesolids are linezolid crystal Form II.

What is claimed is: 1.(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, crystal “Form II ” with a powder X-ray diffraction spectrumof: d-Spacing (Á) Two-Theta Angle (°) Relative Intensity (%) 12.44 7.102 9.26 9.54 9 6.37 13.88 6 6.22 14.23 24 5.48 16.18 3 5.28 16.79 1005.01 17.69 2 4.57 19.41 4 4.50 19.69 2 4.45 19.93 6 4.11 21.61 15 3.9722.39 23 3.89 22.84 4 3.78 23.52 7 3.68 24.16 1 3.52 25.28 13 3.34 26.661 3.30 27.01 3 3.21 27.77
 1.

2.(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, crystal “Form II” with an infrared (IR) spectrum as a mineraloil mull: 3364, 1748, 1675, 1537, 1517, 1445, 1410, 1401, 1358, 1329,1287, 1274, 1253, 1237, 1221, 1145, 1130, 1123, 1116, 1078, 1066, 1049,907, 852 and 758 cm⁻¹.